DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-20 were previously pending.
Receipt is acknowledged of the claim amendments submitted on 25 August 2026. Claims 1-13, and 16 are amended. Claim 15 is canceled. Therefore, claims 1-14, and 16-20 are pending in the instant application.
Applicant's election with traverse of the invention of group I (claims 1-12) drawn to a use of mitochondria and the species (5) of improving mitochondrial membrane potential of gingival fibroblasts in the reply filed on 25 August 2026 is acknowledged. The traversal is on the grounds that the inventions and species can be reasonably searched together. This is not found persuasive because the instantly filed application was filed under 37 CFR 371. As stated in 1893.03(d), unity of invention (not restriction) practice is applicable in such cases. Search burden is not a criteria in 371 cases. Additionally, applicants argue that the composition of claim 1 has been amended to comprise extracellular matrix or extracellular vesicles and Yan (CNl 13633662), merely discloses an application of mitochondria, thus the invention of claim 1 is not anticipated by Yan. This is not persuasive because the amended claims filed by Applicants on 08/25/2026 do not provide evidence that the previously filed claims of 09/06/2024 share a special technical feature over the prior art of Yan (CNl 13633662), and the standard for restriction under 35 U.S.C. 121 and 372 has been improperly applied.
The requirement is still deemed proper and is therefore made FINAL.
It is noted that the species (5) of improving mitochondrial membrane potential of gingival fibroblasts is being applied to all pending claims for the purpose of evaluating compliance with title 35 of the United States Code.
Claims 3-6, 9, 13-14, and 16-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention/species, there being no allowable generic or linking claim.
Therefore, claims 1-2, 7-8, and 10-12 are pending and under examination in the present Official Action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/CN2023/094569, filed 16 May 2023, which claims priority to United States provisional Application No. 63/342,568, filed 16 May 2022. Acknowledgment is made of applicant’s claim for priority.
The earliest possible priority for the instant application is 16 May 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06 September 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings submitted on 06 September 2024 are accepted by the Examiner.
Examiner’s Comment
Throughout the present Official Action, where reference is made to the instant specification, the Examiner will be referring to the publication of the instant application (US 20250205285).
Claim Objections
Claim 2 objected to because of the following informalities: “Leukoplakia” should not be capitalized. While appropriate to capitalize in a medical writing context, capitalization of leukoplakia is not a necessity for proper English. In the presently recited list, leukoplakia should not be capitalized because doing so disrupts the consistency of the claim language. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7 and 10-12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 7 recites the limitation "the mitochondrial membrane potential of gingival fibroblasts" in the second line of the claim. There is insufficient antecedent basis for this limitation in the claim. Neither claim 7 nor claim 1 from which claim 7 depends, recites a mitochondrial membrane potential of gingival fibroblasts to provide antecedent for the claim recitation reproduced here. Thus, there is insufficient antecedent basis for "the mitochondrial membrane potential of gingival fibroblasts" in claim 7 and a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought.
Claim 10 recites “the extracellular vesicles are derived from platelet-rich plasma (PRP) or stem cells”. It is unclear what steps are encompassed by the term “derived from” and a person having ordinary skill in the art would not be able to determine when extracellular vesicles would be considered “derived from” PRP or stem cells to fall within the scope of claim 10. Accordingly, the metes and bounds of claim 10 cannot be determined. Claims 11-12 are further rejected for their dependency on a rejected base claim. Recitation of term “obtained or isolated from” in place of derived would obviate the basis of this rejection.
Claim 12 recites “the mitochondria and the extracellular vesicles are derived from the same stem cells”. It is unclear what steps are encompassed by the term “derived from” and a person having ordinary skill in the art would not be able to determine when extracellular vesicles and mitochondria would be considered “derived from” the same stem cells to fall within the scope of claim 12. Accordingly, the metes and bounds of claim 12 cannot be determined. Recitation of term “obtained or isolated from” in place of derived would obviate the basis of this rejection.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 7-8, and 10-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
A method for improving the mitochondrial membrane potential of gingival fibroblasts in vitro, comprising administering a composition into a culture of gingival fibroblasts, wherein the composition comprises: 15 to 40 μg of mitochondria; and extracellular matrix or extracellular vesicles, wherein the gingival fibroblasts are human gingival fibroblasts, wherein the mitochondria are isolated from human adipose-derived mesenchymal stem cells (ADSCs), wherein the extracellular matrix comprises human extracellular matrix components, and wherein the extracellular vesicles are extracellular vesicles from platelet rich plasma (PRP) or mesenchymal stem cells (MSCs),
does not reasonably provide enablement for (1) a method for improving the mitochondrial membrane potential of gingival fibroblasts in vivo, nor (2) any method for improving the mitochondrial membrane potential of gingival fibroblasts comprising administering any amount of mitochondria (3) from any species to (4) any cells other than human gingival fibroblasts alongside (5) any extracellular matrix other than human extracellular matrix or (6) any extracellular vesicles sourced from any source other than PRP or ADSCs, nor (7) a method for mitigating any oral damage. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
1) Nature of invention. The instant claims as elected are drawn to method for improving the mitochondrial membrane potential of gingival fibroblasts comprising administering a composition comprising mitochondria and either extracellular matrix (ECM) or extracellular vesicles (EVs) into an individual. Thus, the nature of the invention is to improve the mitochondrial membrane potential of gingival fibroblasts via an in vivo method of administering mitochondria.
2) Scope of the invention. The scope of the invention is vast, encompassing any route of administration of any amount of mitochondria from any species to any cells alongside any extracellular matrix or any extracellular vesicles sourced from any cell. It is noted that the scope of the invention is particularly drawn to in vivo methods of administration because the claims require administration of the composition to an individual. Further, the invention encompasses any conceivable “individual” (this can be any animal which is known to have or yet to be understood as having a cell which can be considered a gingival fibroblast), and oral damage not associated with a mitochondria (for example: cavities, chipped teeth, missing teeth, deteriorated jaw bone). The breadth of the claims is perhaps best exemplified by several examples of what the claims encompass. The claims encompass, for example, a method for mitigating a cavity by improving the mitochondrial membrane potential of gingival fibroblasts comprising spraying a composition comprising mitochondria from a plant into the hair of an elephant shrew wherein the composition also comprises extracellular vesicles produced via mechanical disruption of hematopoietic stem cells from a fish. They also encompass a method for improving the mitochondrial membrane potential of gingival fibroblasts comprising injecting 500 kg of mitochondria into the heart of an alligator wherein the mitochondria are encompassed within a gel comprised of amphibian ECM. Consequently, the scope of the instant claims as elected is vast encompassing innumerable species of the method claimed.
3) Number of working examples and guidance. The specification teaches only three working examples for a method for improving the mitochondrial membrane potential of gingival fibroblasts (Specification, [0088]-[0091]). The three examples differ only in that the first of them comprises the administration of mitochondria with ECM whereas the second comprises the administration of mitochondria with PRP EVs and the third comprises the administration of mitochondria with MSC EVs (Specification, [0089], [0090]-[0091]). Each of the three working examples is in vitro. Each of the three working examples uses only mitochondria from human ADSCs expressing CD73, CD90, and CD105 without expressing CD34 or CD45 wherein the mitochondria are extracted from the cells using a mitochondrial isolation kit (Specification, [0055]). Where ECM is used, the working examples only teach MaxGelTM ECM which is a human ECM (Specification, [0056]). The specification is silent as to the species origin of the PRP but teaches that the MSC EVs are isolated from the same human ADSCs that the mitochondria were isolated from (Specification, [0057]-[0058]). Notably, all three working examples were carried out in vitro on cultured human gingival fibroblasts damaged with urban particulate matter to model dental damage (Specification, [0060]-[0061]). None of the three working examples teach any in vivo method. None of the three working examples teach any mitochondria other than mitochondria isolated from human ADSCs. None of the working examples teach ECM other than human ECM. None of the working examples teach EVs other than human PRP or ADSC EVs. Where an amount of mitochondria is taught in the working examples, it is only either 15 or 40 μg of mitochondria (Specification, Tables 13-15). Thus, no working example is provided which teaches the administration of, for example, 40mg of mitochondria as encompassed by the instant claims as elected.
Consequently, while the scope of the claims is comparably vast, the working examples provided to support such a scope are limited to only three examples using very specific amounts of very specific components in an in vitro context. Thus, the skilled artisan would have to look to the art at the time of filing to guide them in practicing the breadth of the genus of methods claimed.
4) State of the art. At the time of filing, it was known that mitochondrial dysfunction was associated with a wide spectrum of diseases owing to the fundamental role of mitochondria in regulating inflammation (Spring Hatfield, Oral-Systemic Links: How Does Mitochondrial Dysfunction Interact with Periodontal Disease?, Today's RDH, published: 04 December 2021, hereinafter "Hatfield", page 2 last paragraph). Hatfield teaches that at the time of filing, the association between mitochondrial dysfunction and periodontal disease had been known for some time (since as far back as 2011) (Hatfield, page 4). Contemporary metanalyses focusing on the relationship between mitochondrial dysfunction and oral inflammatory diseases didn't discuss the direct application of mitochondria as a treatment for said diseases but focused instead on indirect treatments of the mitochondrial dysfunction (Dong et al., Int. J. Mol. Sci. 2023, 24, 15483, hereinafter "Dong", "mitochondrial Dysfunction in the Pathogenesis, Progression and Treatment of OIDs" heading). Dong observed that, as recently as September 2023 (after the filing of the instant Application), "current studies are insufficient to describe the exact role of mitochondrial disfunction in [oral inflammatory diseases]. For example, whether mitochondrial dysfunction occurs before or after clinical symptoms are shown remains unclear…Novel therapeutic approaches, like mitochondria transfer from healthy donor MSCs, have been investigated in treating pulpitis both in vivo and in vitro. However, the therapeutic strategies mentioned above failed to provide data on the long-term prognosis, and the mechanisms of how improvement in mitochondrial dysfunction affects the prognosis of OIDs were poorly investigated" (Dong, "Discussion and Conclusions" heading). Thus, methods of treating oral disease by applying mitochondria directly to an individual were in a nascent state at the time of filing and the state of the art was incomplete with regard to the exact timing of mitochondrial dysfunction with respect to clinical presentation in oral inflammatory diseases and with regard to the underlying mechanisms and appropriate therapeutic strategies for treating oral inflammatory diseases via treatment of mitochondrial dysfunction.
5) Unpredictability of the art. There are four issues with the claims as elected. As a first issue, it is not clear that the disclosure demonstrates a method for improving the mitochondrial membrane potential of gingival fibroblasts in vivo. The “predictability or lack thereof” in the art refers to the ability of one skilled in the art to extrapolate the disclosed or known results to the claimed invention. If one skilled in the art can readily anticipate the effect of a change within the subject matter to which the claimed invention pertains, then there is predictability in the art. On the other hand, if one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art. Accordingly, what is known in the art provides evidence as to the question of predictability M.P.E.P. § 2164.03. It is well known in the art that the translation of in vitro findings to an in vivo context is a difficult endeavor owing to the relative simplicity of in vitro systems (Saeidnia, Soodabeh et al. “From in vitro Experiments to in vivo and Clinical Studies; Pros and Cons.” Current drug discovery technologies vol. 12,4 (2015): 218-24, Abstract provided, hereinafter “Saeidnia”). Saeidnia teaches that the absence of biokinetics in in vitro methods may lead to a misinterpretation of the data and that finding an end point and extrapolation of the effects to the human are some real weaknesses (Saeidnia, Abstract). Thus, the skilled artisan would not be able to readily anticipate the effect of the leap from the in vitro findings of the instant invention to an in vivo human environment, let alone any in vivo environment as currently claimed. At the time of filing, mitochondrial transplantation as a therapy for mitochondrial diseases was a known therapeutic strategy (Zhang et al., Acta pharmaceutica Sinica. B vol. 13,3 (2023): 1028-1035, hereinafter "Zhang"). However, Zhang teaches that isolated mitochondria can only stay active for 1 to 2 hours limiting the application range for the mitochondria and limiting mitochondrial transplantation to only relatively short duration surgeries (Zhang, page 1033, “Challenges”). Zhang also teaches the importance of autologous mitochondria to limit transplantation rejection, and the possibility of increasing inflammation is allogeneic mitochondria are used (Zhang, page 1033, “Challenges”). While Zhang teaches transplantation in a mitochondrial disease context, the teachings are applicable to any other context where mitochondrial transplantation is proposed (like in the instant invention). Further, while Zhang is published after the filing date of the instant invention, the passages relied upon herein cite only to prior art published before the effective filing date of the instant invention. Thus, Zhang teaches the challenges associated with mitochondrial transplantation that the skilled artisan would have to overcome when adapting in vitro findings to an in vivo context. This further supports the conclusion that the skilled artisan would not be able to readily anticipate the effect of the leap from the in vitro findings of the instant invention to an in vivo human environment, let alone any in vivo environment as currently claimed.
As a second issue, it is not clear that the disclosure demonstrates any method for improving the mitochondrial membrane potential of gingival fibroblasts comprising administering any amount of mitochondria. The specification only teaches working examples in vitro which utilized either 15 or 40 μg of mitochondria. The claims as elected encompass any amount of mitochondria greater than or equal to 15 μg. At the time of filing, it was known that mitochondria was typically administered in a μg range in mitochondrial transplantation therapies (Li et al., Biomaterials translational vol. 6,1 (2025): 4-23, hereinafter “Li”, Table 1). Li cites to various studies published before, at, and after the filing date of the instant application in Table 1. None of the studies cited by Li use anything higher than a μg amount of mitochondria (let alone a kg as encompassed by the claims as elected). Notably, no studies are presented for mitochondrial transplantation in a dental context in Table 1 of Li. Thus, the skilled artisan would not be able to readily anticipate the effect of increasing the amount of mitochondria to a level higher than the 40μg displayed in the working examples of the instant application (particularly when considering the leap from in vitro to in vivo).
As a third issue, it is not clear that the disclosure demonstrates any method for improving the mitochondrial membrane potential of gingival fibroblasts comprising administering mitochondria from any species. Mitochondria vary significantly in weight depending on the species the mitochondria are sourced from (Cooper GM. The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates; 2000, hereinafter "Cooper", page 2, last paragraph). Cooper teaches that the genomes of mitochondria of humans are only about 16kb whereas plant mitochondria genomes can be more than 200kb and yeast mitochondria genomes can be about 80kb (Cooper, page 2, last paragraph). The skilled artisan understands that the weight of a single mitochondria varies proportionally with the genome of that mitochondria since the genome itself has a weight. Thus, a plant mitochondria would way significantly more than a human mitochondria at a relative mitochondria genome ratio of 200:16. Thus the skilled artisan would not be able to readily anticipate the effect of using mitochondria from different species than the human mitochondria exemplified since to use a plant mitochondria would present a composition with comparably few mitochondria at 15 μg total.
As a fourth issue, it is not clear that the disclosure demonstrates any method for improving the mitochondrial membrane potential of gingival fibroblasts comprising administering mitochondria to any cells other than human gingival fibroblasts alongside any extracellular matrix other than human extracellular matrix or any extracellular vesicles sourced from any source other than PRP or ADSCs. As discussed directly above, the hurdles the skilled artisan would have to overcome to be able to predictably improve the mitochondrial membrane potential of gingival fibroblasts using the disclosure as a starting point and the art at the time of filing are steep. Compounding the factors already discussed above with administration of the mitochondria to any cells other than the human gingival fibroblasts exemplified in the disclosure alongside any ECM other than the human ECM exemplified in the disclosure or alongside any EVs other than the PRP EVs or ADSC EVs exemplified in the disclosure compounds the already unpredictable nature of the instant invention. The skilled artisan would not be able to readily determine the effects of changing any of these further variables when translating the in vitro results of the present application to an in vivo context.
As well, the claims are drawn to an incredibly large genus of in vivo methods. The physiological art is recognized as unpredictable. (MPEP 2164.03.) In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved. It is not a question of safety but one of predictability.
6) Amount of Experimentation Required. The claims have been evaluated in light of the art at the time of filing and found not to be commensurate in scope with the specification. MPEP 2164.05 teaches, “However, the examiner should carefully compare the steps, materials, and conditions used in the experiments of the declaration with those disclosed in the application to make sure that they are commensurate in scope; i.e., that the experiments used the guidance in the specification as filed and what was well known to one of skill in the art. Such a showing also must be commensurate with the scope of the claimed invention, i.e., must bear a reasonable correlation to the scope of the claimed invention.
Consequently, the prior art (and post-filing art) when combined with the lack of any disclosed direct experimental test of an in vivo application of Applicant’s in vitro findings, shows that one of skill in the art at the time the invention was made would have had no basis to reasonably predict or conclude the claimed methods for improving the mitochondrial membrane potential of gingival fibroblasts could be identified given the lack of details necessary to identify those meeting the necessary functions. Though not controlling, the lack of working examples is, nevertheless, a factor to be considered in a case involving both physiological activity and an undeveloped art. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, he runs the risk that unless one with ordinary skill in the art would accept the allegations as obviously valid and correct, the PTO may, properly, ask for evidence to substantiate them. Ex parte Sudilovsky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971).
Given the widely divergent nature of the methods of improving the mitochondrial membrane potential of gingival fibroblasts that are encompassed by the claims, and the uncertainty in the translation of in vitro findings to the in vivo environment, particularly when considering the breadth of the variables claimed, it must be considered that these must be empirically determined. Further, in an unpredictable art, the disclosure of limited examples utilizing only in vitro conditions with specific amounts of mitochondria from specific species alongside specific ECM or EVs from the same specific species applied to gingival fibroblasts from the same specific species (humans) would require the skilled artisan to undertake undue experimentation to practice the breadth of the invention claimed.
Additional Comments
The closest prior art to the instant invention is CN 113633662 (published: 12 November 2021, hereinafter “Wang”, Of record on the IDS submitted 06 September 2024, English Machine Translation attached). Wang teaches the application of mitochondrial transplantation to the treatment of periodontitis (Wang, Abstract). Wang teaches in vitro experiments supporting the application of mitochondrial transplantation to periodontitis treatment (Wang, Abstract; “Contents of the Invention” heading). Wang does not teach to administer the mitochondria to a culture of human gingival fibroblasts alongside ECM or EVs (identified as the enabled claim scope above).
Conclusion
No claim is allowed.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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